Landscape Analysis of CLDN18 Expression and Isoform Distribution in Solid Tumors: Insights From MONSTAR‐SCREEN‐2 Study
Hashimoto T., Iida N., Nakamura Y., Nonomura N., Morizane C., Iwata H., Okano S., Yamagami W., Yamazaki N., Kadowaki S., Ueno M., Boku S., Oki E., Komatsu Y., Yuki S., Makiyama A., Ogata T., Takahashi N., Okano N., Nishina T., Sakamoto N., Kuwata T., Yamashita R., Shibuki T., Imai M., Fujisawa T., Bando H., Shitara K., Yoshino T.
ABSTRACTClaudin 18.2 (CLDN18.2), a tight junction protein isoform, is an emerging therapeutic target in oncology. CLDN18 is well‐characterized in gastric cancer, but its pan‐cancer expression profiles and isoform distributions are poorly documented. In the present study, we analyzed CLDN18 expression in patients with solid tumors enrolled in the MONSTAR‐SCREEN‐2 study using immunohistochemistry (IHC, n = 349) and whole‐transcriptome sequencing (WTS, n = 2191). A splice junction analysis algorithm characterized isoform distribution patterns in WTS data and evaluated temporal changes using paired pre‐ and postchemotherapy specimens. IHC detected CLDN18.2 (≥ 40% of tumor cells showing any staining intensity) in 16.3% of patients, with highest prevalence in gastric (54.5%), biliary tract (21.7%), pancreatic (20.7%), and small intestinal (18.2%) cancers. WTS and IHC findings were significantly correlated (p < 0.001). WTS analysis with optimized transcript thresholds (n = 2191) demonstrated the CLDN18‐high population to be 13.8%, with highest proportions in gastric (64.5%), small intestinal (40.0%), pancreatic (37.8%), and biliary tract (20.0%) cancers. Isoform analysis of 364 patients revealed CLDN18.2 predominance (mean 18.2/18.1 proportion 0.945), with CLDN18.1 predominance observed in only 4.9% of patients. Longitudinal analysis of 27 paired gastric cancer samples revealed a significant reduction in CLDN18 expression and a nonsignificant decrease in the CLDN18.2 proportion following chemotherapy. This analysis validates WTS as a complementary approach to IHC for CLDN18 assessment and demonstrates significant CLDN18 expression across multiple cancer types. The predominance of CLDN18.2 supports the expansion of targeted therapeutic approaches beyond gastric cancer and indicates the potential of RNA‐based screening.